Download Clairvoyance and Caution

Click here to
DONATE TO
OUR EFFORT
Clairvoyance and Caution
Nancy S. Wexler
(condensed)
Clairvoyance and Caution:
Repercussions from the Human Genome Project
The Code of Codes: Scientific and Social Issues in the Human Genome Project. D.J. Kevles
and L. Hood (Eds) Harvard University Press, 1992, 211-243
The natural trajectory of human genome research is toward the identification of genes, genes that control
normal biological functions and genes that create genetic disease or interact with other genes to precipitate
hereditary disorders. Genes are being localized far more rapidly than treatments are being developed for the
afflictions they cause, and the human genome project will accelerate this trend. The acquisition of genetic
knowledge is, in short, outpacing the accumulation of therapeutic power -- a condition that poses special
difficulties for genetic knowing.
Our expectation is that the characterization of a disease- instigating gene will greatly assist our understanding
of how and why it causes a malfunction in the body. It makes good sense to go to the root of the problem. But
to learn a gene's secret, first you must find it. And finding it is not so simple. It is much easier to locate the
neighborhood in the genome where a gene resides than it is to determine its exact address.
Lilliput and Brobdingnag: Beyond Gulliver's Travels. The magnitude of the challenge arises from the vast
amount of DNA contained in the diploid human genome, which includes all of a person's genetic material. If
strung out, the DNA in a single human genome would stretch to about two meters, but the diameter of the
strand would amount to only about two billionths of a meter, 20 angstroms, a span a hundred times smaller
than a wavelength of light. If the DNA from a single cell from every human being on the planet -- 6 billion
people -- were stitched end to end, the resulting string would girdle the earth about 300 times. If the genomes
from every cell of the 6 billion people were laid out end to end, they would extend 700 billion, billion miles --
enough to wrap around our galaxy more than 700 times.
To understand the enormous problem of finding a gene somewhere on an individual's strand of DNA, imagine
that a single human genome is long enough to circle the globe. On this scale, the amount of DNA in a
chromosome would extend for a thousand miles. A gene would span just one twentieth of a mile, and a
disease-causing defect -- a point mutation, a change in only one DNA base pair -- could run as short as one
twentieth of an inch. What we are thus searching for is comparable to a fraction of an inch on the
circumference of the globe! In this immense morass of DNA, finding the exact address of a gene and
pinpointing its fault makes for extremely tough going, and it requires all of the creativity and ingenuity of
everyone engaged in the quest.
Hunting for Huntington's. The spectacular difficulty of the problem has been made painfully clear by the
search for the gene causing Huntington's disease (HD). Huntington's disease is a movement disorder -- causing
uncontrollable jerking and writhing movements of all parts of the body, called chorea. Even more distressing
to patients and families than the obvious movements, it is preceded or accompanied by cognitive changes
leading to profound intellectual deterioration and frequently severe emotional disturbances, usually suicidal
depression and occasionally hallucinations and delusions. The disease runs a course of about fifteen to twentyfive years and is inevitably fatal. Its usual onset is between the ages of thirty-five and forty-five, but it can start
as early as two and as late as the early eighties, an age when it can be hard to detect. The later the onset, the
milder the symptoms. If the diagnosis is missed in an elderly person, manifestation of the disease in the next
generation may appear erroneously to be due to a new mutation. No treatments are known beyond some
marginal and temporary palliation for the movements and anti-depressants for the psychiatric symptoms.
Huntington's disease is the product of a gene transmitted in an autosomally dominant inheritance pattern -- in
other words, a gene that occurs on one of the twenty-two non-sex human chromosomes and whose effect
dominates its normal partner. It is entirely penetrant, which means that if a gene-carrier lives long enough, the
disease is inexorably expressed.
"Riflips" to the rescue. In looking for the fraction of an inch responsible for HD on the globe of DNA, we
get some very clever help from restriction enzymes that identify small, normal variations in DNA called
restriction fragment length polymorphisms -- the RFLPs that geneticists pronounce as "riflips." Whenever a
restriction enzyme sees its unique recognition site, it cuts the DNA right at that spot, like a miniature pair of
scissors. The locations of these sites vary among individuals, and, as a result, the DNA fragments between two
sites differ in length. When DNA is cut with restriction enzymes, these differences in fragment sizes can
differentiate one person from another, one chromosome from another, and they are inherited, just as genes are.
"Riflips" act as markers in a person's DNA, a telltale indicator of genetic identity. (There are now many new
kinds of very informative markers that do not require restriction enzymes but still serve the same function of
identifying specific regions in the DNA.)
When we began the search for the HD gene, we were looking for a RFLP marker that was close to it. We can
get an idea of the relative closeness of a marker and a gene on a chromosome because of a process called
recombination -- the tendency of segments of paired chromosomes (one from the father, the other from the
mother) to change places during the creation of gametes, a kind of genetic "do-si-do." The further apart the
marker is from the gene, the more likely it is that one of these "recombination events" will separate them; the
closer together, the less likely. For every one million base pairs of DNA, there is a 1 percent chance that a
recombination event will take place. Counting the number of recombination events found gives you a fairly
good estimate of genetic distance between two markers or a marker and a gene. (I explain recombination
probabilities to myself by imagining an earthquake at the North Pole where thousands of penguins occupy a
huge ice floe; when the ice breaks up, two penguins sitting next to each other are more likely to stay on the
same little piece of ice while two penguins far away from each other will drift away on separate pieces down
each half of the globe.) If one of these penguins is a DNA marker and the other the HD gene on the same floe,
the two will travel together. If the "penguins" are close on the same chromosome, they will be transmitted to
offspring in a Mendelian fashion with a high degree of regularity. So if a mother with Huntington's disease has
a pattern-A RFLP next to her HD gene, and the father, who is not affected with Huntington's disease, has a
pattern-B RFLP next to his normal gene, then their children with the B pattern will most likely not inherit HD
and those who have inherited the HD gene will show the A pattern. (Because of the possibility that a
recombination event will separate and rearrange markers and genes, we can only say "most likely.")
Venezuela bound. In 1979, despite such sensible advice, we began hunting for the Huntington's disease gene.
We knew that just finding the location of the gene would not tell us anything about the nature of the gene
defect itself. But we reasoned that if we could close in on the gene from either direction, using markers more
and more closely spaced until we finally honed in on the gene itself, we could then direct all our energies and
resources toward identifying the gene defect and developing therapeutic interventions. If we were incredibly
lucky, the markers could tell us, "your murderer is living in Red Lodge, Montana," and then we could continue
the hunt door-to-door.
The only way you can tell if a marker is close to an unmapped gene is to observe if the two consistently
"travel" together in a family. We know certain people have the HD gene because they are sick. We were
looking for people who had the disease to have one form of a marker and their unaffected relatives to have
another form of that same marker. We needed to study large families, as the HD gene itself might vary in its
locale from family to family, and the markers, having nothing to do with disease itself, would certainly vary
across families as to which form of the marker traveled with the gene.
So we were looking for a large extended multigenerational family in which we could observe many instances
of the Huntington's disease gene or its normal counterpart being passed on -- and we knew of just such a
family, although when we began we had no idea how huge and important this family would eventually turn
out to be. Members of the kindred live in Venezuela in three rural villages -- San Luis, Barranquitas, and
Laguneta -- on the shores of Lake Maracaibo. Because it is situated in the northern region of Latin America
and Lake Maracaibo is actually a huge ocean gulf, Venezuela has long communicated directly with Europe,
and many European genes have appeared in the local population. Story has it that some sailor with
Huntington's disease came over to trade and left his legacy, but we do not know if this is apocryphal.
We have been able to trace the disease as far back as the early 1800s, to a woman appropriately named Maria
ConcepciÛn. We know that Maria lived in the "pueblos de agua," villages built on stilts in the water next to
shores too marshy, jungly, and inhospitable to accommodate human life. Laguneta, where many of Maria's
descendants live, remains such a stilt village.
Maria was the founder of a kindred now numbering close to 11,000 people, living and deceased. In the
pedigree, there are 371 persons with Huntington's disease, 1,266 at 50 percent risk and 2,395 at 25 percent risk
for the disease. Of the 11,000, 9,000 are living and the majority are under the age of forty. In these small and
impoverished towns, we estimate that there are over 660 asymptomatic gene carriers who are too young to
show symptoms, but as years pass -- if no treatment is found -- they will surely die. It is crushing to look at
these exuberant children full of hope and expectation, despite poverty, despite illiteracy, despite dangerous and
exhausting work for the boys fishing in small boats in the turbulent lake, or for even the tiny girls tending
house and caring for ill parents, despite a brutalizing disease robbing them of parents, grandparents, aunts,
uncles, and cousins -- they are joyous and wild with life, until the disease attacks. Every year we add more
people to the pedigree who will suffer, diagnose more new cases, and watch helplessly as more and more
begin that sad journey toward deterioration and death. It is impossible to be immune to their plight. It is only
possible to be passionate and driven and work desperately to save as many as we can before it is too late.
I felt it was important for the Venezuelan family members to know that Huntington's disease was also in my
family and in many others in the United States but that our families were not large enough to offer the gift to
research that their family was capable of providing. We needed their help to find a cure. At that time we were
doing skin biopsies, which I also had done for research. The family members were dubious of my story until I
pointed out my skin biopsy scar and my wonderful colleague and friend, Fidela Gomez, a Florida nurse,
grabbed my arm and dragged me around the room shouting, "She has the mark, she has the mark!" My mark
and I became something of a passport for our research team and its activities.
Genetic jackpot. At Massachusetts General Hospital, DNA was extracted from blood samples from the
Venezuelan family members. Jim Gusella was also studying a large American family with Huntington's
disease from Iowa. He searched the DNA from these two families for a telltale marker, helping to develop
what were to become standard laboratory procedures in such ventures. Jim sliced up each person's DNA with
restriction enzymes. He then developed markers, RFLPs, which he made radioactive. These markers were
called anonymous because he did not know on which human chromosome they were located, only that they
were in one unique spot in the genome, just like a gene, and they came in several forms so that individuals
could be differentiated from one another. The fragments of chopped-up DNA from the family members were
put on a gel that separates fragments on the basis of size. The radioactive probe (denatured, or singlestranded) was then added. When the probe is radioactive, it would "light up" where it was stuck on the gel,
revealing distinctive bands. One would then need to check if a certain pattern of bands appeared only in
individuals who had the disease and another pattern in their relatives who were healthy. If this difference was
true more often than would be expected by chance, it would be very likely that the marker and the gene were
close together on the same chromosome.
We all expected that the detection of a marker linked to the Huntington's disease gene would require thousands
of tests and probes, but the third probe that Gusella characterized and the twelfth one he tried hit the jackpot.
He began with the Iowan family, whose samples were the first to be collected, and the probe, called G8, was
weakly positive, but not significantly so.
This finding gave him the crucial push, however, to try G8 in the Venezuelan family -- and it was the only
probe he needed! It immediately showed odds far better than 1,000 to 1 that it was very close to the HD gene.
P. Michael Conneally at Indiana University performed the computer linkage analyses that definitely proved
that this probe and the HD gene were close neighbors. Almost all the Venezuelan family members with HD
had one form of the marker while their healthy relative had another. At the time linkage was discovered, the
chromosomal location of the probe was unknown, but it was quickly mapped, using in situ hybridization and
other techniques, to chromosome 4. By inference, the position of the gene was mapped as well. Out of 3
billion possible base pairs on 23 chromosomes, we now knew we were a mere 4 million base pairs below the
culprit gene way on the very top of the short arm of chromosome 4. We triumphantly announced the feat in an
article in Nature, in November 1983.
It had taken us just three years -- an astonishingly short time -- to localize the HD gene. Our critics and even
our supporters said, rightly, that we had been incredibly lucky. It was as though, without the map of the United
States, we had looked for the killer by chance in Red Lodge, Montana, and found the neighborhood where he
was living.
A new era: Prediction outstrips prevention. While the search for the Huntington's disease gene goes on,
painstakingly, the discovery of markers linked to the gene has opened a new, exciting yet troubling era:
presymptomatic and prenatal diagnosis of Huntington's disease with no cure in sight.
Immediately after localizing the Huntington's disease gene, we confronted the question of genetic
heterogeneity: Is the HD gene in the same chromosomal locale in all families with Huntington's disease
throughout the world? Many other genetic disorders manifest genetic heterogeneity -- the causative gene may
be on several different chromosomes, even though phenotypically the symptoms of the illness appear to be the
same in all the affected families. Was our chromosome 4 home for Huntington's disease unique to the Lake
Maracaibo kindred and an Iowan family, or was it universal? Over one hundred families have been tested from
throughout the world -- in Europe, North and South America, even Paupa, New Guinea -- and in all of them
the HD gene is in the same chromosomal locale on the top of chromosome 4. The actual mutations at that spot
may turn out to differ, but the region is the same. Given its universality, we can now use G8 and other markers
subsequently found closer to the gene to test whether an individual has the HD gene before any symptoms
appear, even before birth. So here we confront our worst fears: our scientific success puts us on the threshold
of an era of unknown but imaginable dangers. We can predict the flood but cannot leave or stop the tide. We
can tell people that they possess the gene and will eventually come down with the disease, but we have no cure
or even therapy to offer to soften the blow.
Genetic illiteracy. In all of these screening programs people must understand the difference between being a
carrier of one abnormal gene for a recessive condition, in which the carrier usually has no symptoms, as
opposed to an affected individual who has two copies of the abnormal gene. People must equally understand
that carriers for a dominant disorder, a late-onset illness such as Huntington's disease or polycystic kidney
disease, will, in fact, get sick. In recessive diseases the carrier will become a patient. How do we explain
technically complex and emotionally charged information to ordinary people, many of whom never heard of
DNA and barely of genes, who have hardly a clue about probability, and whose science education never
equipped them to make choices regarding these matters? How do we ensure justice in access to counseling
services and make them available to more than the white middle and upper classes who typically utilize them
now? Genetic diseases cross ethnic and class boundaries, but access to services, unfortunately, does not.
How do we guarantee that the doctors who test individuals or populations provide adequate genetic counseling
when doctors themselves have minimal training in genetics and often fundamentally misunderstand its
principles? What should we do about doctors who say to a couple with one child affected by cystic fibrosis
and who are contemplating having another, "Don't worry, lightning never strikes twice in the same place." Or - the ultimate in confusion about a genetically dominant disease -- "Don't worry about Huntington's, just tell
'em to marry out into families that don't have it!" Such medical mistakes have increasingly been addressed
through malpractice suits, including wrongful birth and wrongful life cases. In wrongful birth cases, parents of
a seriously impaired child bring an action claiming that the child should never have been born. The parents
argue that they were deprived through the negligence of a health care provider of the information that they
needed to decide whether to initiate or continue a pregnancy. Had they known, they claim, they never would
have had the child. Wrongful life is an action brought by the child claiming that it should never have been
born.4 Must we resort to the threat of lawsuits to ensure that good medical practices will be followed? Or
should we have sufficient ingenuity and imagination to be able to introduce new genetic findings into medical
practice without increasing the litigiousness of our already embattled society? I believe we can figure out how
to offer people genetic information in a way they can understand and assimilate. We can resolve these
difficulties if we start working on them now, before the deluge of new tests the human genome program will
bring.
There are many families in which an insufficient number of genetically informative people are living (or have
banked DNA samples) to permit diagnostic testing for Huntington's disease. And many people would prefer
not to know their own genetic status -- whether or not they will develop HD. Can anything be offered for these
people? One kind of test -- called a nondisclosing prenatal test -- allows couples at risk to gather some
information about a fetus. This test can tell, almost definitively, if a fetus is not going to have HD but cannot
tell definitely if the fetus is carrying the gene.
A person at risk has one chromosome 4 from a parent with HD, the other from a parent without the disease.
The chromosome 4 from the affected parent may or may not be carrying the HD gene. The at-risk individual
will pass on only one chromosome 4 to the fetus; the other comes from the partner. If that chromosome is the
one from the unaffected parent, the fetus has a negligible risk (there is always some risk due to the possibility
of recombination). If that chromosome comes from the affected parent, the fetus has the same risk as the atrisk parent: fifty-fifty. In a nondisclosing prenatal test, the risk status of the at-risk parent is not altered at all.
The only new information that is acquired is whether the fetus has the chromosome 4 that came from its
affected grandparent, in which case it has a fifty-fifty risk, or from its nonaffected grandparent, in which case
its risk is minimal. And all that is required for this test is a DNA sample from the fetus, obtained through
amniocentesis or chorionic villus sampling, both its parents, and one or both parents of the person at risk -- a
minimum of four people. (If the affected grandparent has died, his or her genotype can usually be inferred
from the other individuals available.)
When we first began offering testing for HD, many of us involved in providing the test thought that
nondisclosing prenatal tests would be a preferred option. It offers a chance to ensure that children would be
free of the disease while at the same time protecting individuals at risk from learning potentially traumatic
information. But comparatively few have utilized the test. Its worst aspect is the possibility of aborting a fetus
with a 50 percent probability of not having Huntington's disease, the same risk as the at-risk parent. Just
imagine -- you're pregnant or you've fathered a baby, you're attached emotionally, your fantasies are engaged,
and now you're confronted with the choice of aborting a baby who might be perfectly normal. How easy will it
be for you to become pregnant again? How fast is your biological clock ticking? What if it happens again? A
one in two chance is high. Some people feel that aborting a fetus with a 50 percent risk of HD is equivalent to
aborting themselves, a rejection of who they are and of their legitimate place in the world. This sentiment is
sometimes voiced by those who are disabled, those who object to genetic testing on the grounds that it is
designed to eliminate people like them. Because of these particular difficulties, nondisclosing prenatal testing
must be offered in a context of intensive counseling and support. If the couple is willing and interested, it is
extremely valuable for research purposes to study any tissues resulting from terminations, particularly with
respect to learning more about the timing of the HD gene expression. It is possible that the gene is expressed
only in utero.
A problem arises when identical twins arrive at the testing center and one wants to be tested and the other
does not. Now who should hold sway? One center said, "We'll test you but don't tell your twin." It doesn't
work. If you are free of the disease it would be almost inconceivable not to run to your twin with the good
news. And if the outcome is HD, it's hard to explain uncontrolled crying as a chronic cold to people who know
you well. Other testing centers confronted with this predicament consulted ethicists who gave them
pronouncements that autonomy is higher on the scale of ethical virtues than privacy, so the centers decided to
proceed with the test. But to my mind, autonomy or privacy may be irrelevant if the twin who is not part of the
testing process and has not even had the benefit of counseling learns the truth and commits suicide. The
immediacy of each individual's psychological reality must take precedence over abstract, theoretical values
and issues. One cannot consult a guidebook for who should be tested and under what circumstances. The
professionals giving presymptomatic test counseling must be trained psychotherapeutically to help determine
the best solutions for individuals and families as a whole.
Another factor that is insufficiently appreciated is that when one person in a family is tested, the entire family
is tested and all must live with the outcomes. Many parents of persons at risk feel guilty about and responsible
for their children's risk status, even though they may have known nothing about HD when the children were
born. In some families, three or four children simultaneously may be diagnosed presymptomatically. A parent
who has spent fifteen or twenty years caring for an ill spouse now has a grim preview of the future: the
prospect of caring for children as well, or knowing that the children may have to depend on the mercy of
strangers. One woman said, "When my husband died after twenty-five years of illness, I felt like a light had
finally come on at the end of the tunnel. Now I watch my daughter and see her movements and the light has
extinguished."
But parents do advance cogent arguments for testing their minor children -- they need the information for
making financial and other life plans. It would certainly make a difference to know that any or all of your
children are going to develop HD. Withholding this information from parents goes against the typical situation
found in family case law, in which parents are entitled to medical information and the only instances in which
the courts are likely to intervene is when parents are not providing medical attention for religious or other
reasons.5 One of the complexities of providing nondisclosing prenatal testing is that it sometimes forces you
to give information about a minor child despite your protocol. Prenatal testing for HD is not offered to couples
who have no intention of terminating the pregnancy because there is no medical advantage to the parents to
have this information, and because prenatal testing does pose a slight medical risk to the fetus and entails
testing a minor without its consent. But if a couple finds that their fetus has a 50 percent risk of having HD,
they still may change their minds about a termination and carry the pregnancy to term. If the at-risk parent
later develops the disease, the genetic identity of the fetus is also revealed. This violation of the privacy of the
minor must be endured because parents are entitled to change their minds regarding the termination of a
pregnancy. But very careful counseling must be provided so that the couple knows exactly what the test
involves and the nature of their options.
One group of individuals who come for testing I call the "altruistic testees." These are people who would
prefer not to be tested but are doing so to clarify the risk for their children who are getting to be dating or
marrying age. The genetic risk for these people is lower because they are older, but many of them really do not
want to be tested and would prefer not to "rock the boat." We know very little about the response of this group
to a diagnosis of probably gene-positive.
Some clients who learn that they do not carry the disease gene find that this knowledge does not make all of
their problems disappear. They may still have trouble finding the "right person" or managing their careers.
Before the test, being at risk became a convenient excuse for putting decisions on hold, for postponing and
avoiding issues that may have nothing to do with being at risk but become entangled in the risk situation.
People at risk say, "Well, if I just weren't at risk, I could figure this all out." Then, suddenly, they are no longer
at risk, but they still can't figure things out. The problems have become too entrenched, too much a part of
their characters.
This is not to say that good news does not also lead to ecstasy and joy. Some people alter their lives -- have
children, move, or change jobs -- and feel wonderful about the change. Others experience a kind of survival
guilt and sense of unease with respect to other family members who may not know their genetic status or who
tested positive for the gene.
Presymptomatic testing: preliminary outcomes. Our experience with genetic diagnostic testing for
Huntington's disease in our own country suggests that, with very intensive counseling, the few people who
have tested positively tend, by and large, to do pretty well. In Canada, one person who came for
presymptomatic testing and discovered she was already symptomatic made a suicide attempt, and there has
been one hospitalization in the United States that I know of for severe depression following a presymptomatic
positive diagnosis. Most people who have tested most likely positive for the presence of the gene have had this
news for only a year or two, and we have no idea how this group will respond once they find themselves
becoming symptomatic. One woman told me she was often asked if she regretted her decision to be tested. She
added, "You know, I don't think so, but I really can't afford to think about that question too long because I'm
afraid it's going to take up housekeeping in my mind."
We are unable to tell people when the disease will start; we can just say that they most likely have the gene. In
follow-up interviews some time after testing, people who have tested positive were asked if they think they
will develop the disease; some reply, "I don't think so, because God will cure me, or science will cure me, or
the test was wrong."9 It is traumatizing to be totally healthy and know with almost 100 percent certainty that
Huntington's disease is in your future.
A person taking a genetic test makes a terrific gain-loss calculation. The gain, obviously, is to learn that you
do not have the genes for Alzheimer's, cystic fibrosis, Huntington's, or any number of other diseases. The loss
is to learn that you do. Is learning the good news worth risking hearing the bad? Many who come for testing
already feel they are in a loss position; they consider being at risk just as bad as knowing they will be affected.
They assume they cannot do one thing or another because they are at risk, even though they could do what
they want. Nothing is really stopping them, but they are paralyzed by their risk situation: because certain
things are unknown, everything becomes impossible. I asked a woman why she wanted to be tested. She
replied, "If I find out I'm going to have HD, I'll take my son to Hawaii; but if I'm OK, then I'll wait." I said, "If
you want to take your son to Hawaii, why are you waiting until you get diagnosed with HD to do it? Because
by the time that you're ready to take him to Hawaii, he's going with his girlfriend, not his mother." Since many
people at risk already feel themselves to be in a loss situation, they are more willing to take a test which may
throw them for a greater loss -- learning that they do, in fact, carry the gene. If they see their lives more or less
in a gain situation -- they have chosen their careers, had their children -- then they are more conservative about
maintaining that gain and not willing to take the gamble. Some people will take the gamble for the sake of
their children, because the only way to clarify their risk is to take the test.
What makes these problems so difficult is the absence of recourse to treatment. If you can do something about
the disease, then there will be an incentive to undergo presymptomatic testing and the catastrophic nature of a
positive diagnosis will be tempered. If the treatment is only marginal, the choice to be tested will still be
difficult. Attitudes toward HIV testing changed when people learned that the drug AZT could retard disease
onset in individuals positive for HIV.
The human genome project: Road map to health. The human genome project should eventually point the
way to preventions and cures. The project should, within the next few years, establish an "index" map of the
human genome, with markers spaced about every 10 million base pairs, placing at least one marker close
enough to every gene of interest to locate it. This map should get us in the neighborhood of most diseasecausing genes. Then will follow the construction of a "high-resolution" map, one with thousands of markers
spaced every million or so base pairs. With this detailed map, it should be possible to localize genes more
rapidly and precisely, and finding the genes should lead to their sequencing and characterization. This map
will guide the "gene hunters" as they navigate along the genome.
Ethical, legal, and social issues. There are many social, psychological, ethical, legal, and economic problems
awaiting us that I have not even mentioned. Once we have improved capacity to diagnose disorders
presymptomatically, many more individuals and families may face the loss of health and life insurance. They
may be exposed to discrimination from employers and stigmatization and ostracism from friends and relatives.
Predictive information can be fraught with dangers to individuals and to society. To address these concerns,
the National Center for Human Genome Research, the National Institutes for Health, and the Human Genome
Program of the Department of Energy have established the Joint Working Group on Ethical, Legal, and Social
Issues associated with mapping and sequencing the human genome. It is the mandate of this working group to
support research in these critical arenas and develop policy recommendations for the necessary protections
that must be put in place as new genetic tests are being developed.
If there are so many personal, social, and economic hazards and successful cures are not assured, some people
ask, why proceed with the project? How can we not proceed? Many who suffer from hereditary diseases
already make huge economic sacrifices, already pay exorbitant psychological and social costs. I could not go
to Venezuela and say to those expectant people, "Sorry, we've called off the research for the Huntington's
disease gene because having the gene in hand is too dangerous and there is no guarantee of a cure." I am an
optimist. Even though I feel that this hiatus in which we will be able only to predict and not to prevent will be
exceedingly difficult -- it will stress medical, social, and economic systems that were already under a severe
strain before the advent of the human genome project -- I believe that the knowledge will be worth the risks.
We are learning from our experience with Huntington's disease and other disorders about the power of
clairvoyance and the need for caution. We are preparing for the future when tests for breast cancer, colon
cancer, heart disease, Alzheimer's disease, manic depression, and schizophrenia might well be available. For a
while we may have the worst of all possible worlds -- limited or no treatments, high hopes and probably
unrealistic expectations, insurance repercussions -- everything to challenge our inventiveness and stamina. But
these ingredients will be, I hope, catalysts for change. The stakes are high; the payoff is high. I am reminded
of a line by the poet Delmore Schwartz: "In dreams begin responsibilities."
REFERENCES
1. James Gusella, Nancy Wexler, P. Michael Conneally, et al., "A Polymorphic DNA Marker GeneticallyLinked to Huntington's Disease," Nature, 306 (1983), 234-238.
2. Johanna M. Rommens et al., "Identification of the Cystic Fibrosis Gene: Chromosome Walking and
Jumping," Science, 245 (September 8, 1989), 1059-1065; John R. Riordan et al., "Identification of the Cystic
Fibrosis Gene: Cloning and Characterization of Complementary DNA," ibid., pp. 1066-1073; Bat-Sheva
Kerem et al., "Identification of the Cystic Fibrosis Gene: Genetic Analysis," ibid., pp. 1073-1080.
3. C.T. Caskey et al., "The American Society of Human Genetics Statement on Cystic Fibrosis Screening,"
American Journal of Human Genetics, 46 (1990), 393; B.S. Wilfond and N. Fost, "The Cystic Fibrosis Gene:
Medical and Social Implications for Heterozygote Detection," Journal of the American Medical Association,
263 (May 23/30, 1990), 2777-2783; Workshop on Population Screening for the Cystic Fibrosis Gene,
"Statement from the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis
Gene," New England Journal of Medicine, 323 (July 5, 1990), 70-71.
4. Lori B. Andrews, "Legal Aspects of Genetic Information," Yale Journal of Biology and Medicine, 64
(1991), 29-40; N.S. Wexler, "Will the Circle Be Unbroken? Sterilizing the Genetically Impaired," in A.
Milunsky, ed., Genetics and the Law (New York: Plenum Press, 1980); Nancy S. Wexler, "The Oracle of
DNA," in L.P. Rowland, ed., Molecular Genetics in Diseases of Brain, Nerve, and Muscle (New York: Oxford
University Press, 1989).
5. Symposium, "A Legal Research Agenda for the Human Genome Initiative," Arizona State University,
Center for the Study of Law, Science and Technology, May 17- 18, 1991.
6. Reported in Marc Lappe, Genetic Politics (New York: Simon and Schuster, 1977).
7. G. Stamatoyannopoulos, "Problems of Screening and Counseling in the Hemoglobinopathies," A.G.
Motulsky and W. Lenz, eds., Birth Defects (Amsterdam: Excerpta Medica, 1974), pp. 268-276.
8. A. Cao et al., "Prevention of Homozygous Betathalassemia by Carrier Screening and Prenatal Diagnosis in
Sardinia," American Journal of Human Genetics, 33 (1981), 593-605.
9. Personal communication, Dr. Jason Brandt, Johns Hopkins Hospital, Baltimore, Md.
10. Amos Tversky and Daniel Kahneman, "The Framing of Decisions and the Psychology of Choice,"
Science, 211 (1981), 453-458.
11. Melissa A. Rosenfeld et al., "Adenovirus-Mediated Transfer of a Recombinant -Antitrypsin Gene to the
Lung Epithelium in Vivo," Science, 252 (April 19, 1991), 431-434.
12. Mitchell L. Drumm et al., "Correction of the Cystic Fibrosis Defect in Vitro by Retrovirus-Mediated Gene
Transfer," Cell, 62 (September 21, 1990), 1227-1233; D.P. Rich et al., "Expression of Cystic Fibrosis
Transmembrane Conductance Regulator Corrects Defective Chloride Channel Regulation in Cystic Fibrosis
Airway Epithelial Cells," Nature, 347 (September 27, 1990), pp. 358-363.
13. Natalie Angier, "Team Cures Cells in Cystic Fibrosis by Gene Insertion," New York Time, September 21,
1990, p. A1.